Decorin deficiency promotes epithelial-mesenchymal transition and colon cancer metastasis.
Decorin deficiency promotes epithelial-mesenchymal transition and colon cancer metastasis.
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DOI：
10.1016/j.matbio.2020.10.001
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Bi X
中科院分区：
文献类型：
--
作者：
Mao L;Yang J;Yue J;Chen Y;Zhou H;Fan D;Zhang Q;Buraschi S;Iozzo RV;Bi X
肿瘤微环境包含复杂的细胞网络，包括癌症相关的成纤维细胞、炎性细胞、新血管和富含血管生成生长因子的细胞外基质。核心蛋白聚糖是肿瘤间质的主要成分之一，但它不被癌细胞表达。这种蛋白聚糖的缺乏与E-钙粘蛋白的下调和β-连环蛋白信号传导的诱导相关。在这项研究中，我们研究了核心蛋白聚糖缺陷的肿瘤微环境在结肠癌进展和转移中的作用。我们通过对成年野生型和Dcn−/−小鼠给予氧化偶氮甲烷/葡聚糖硫酸钠，建立了结肠炎相关癌症模型。我们发现，12周后，所有的动物都发生了肠道肿瘤，与它们的基因型无关。然而，维斯野生型小鼠维斯，Dcn−/−微环境中的肠道肿瘤数量显着增加。从机制上讲，我们发现在未受到挑战的基础条件下，Dcn−/−小鼠的肠上皮细胞显示上皮-间质转化相关因子（包括Snail、Slug、Twist和MMP 2）的蛋白水平显著增加。相比之下，在Dcn−/−小鼠诱发的结肠炎相关癌症中，我们发现细胞间粘附分子1（ICAM-1）也显著增加，与上皮-间质转化信号通路相关因子平行。此外，塞来昔布/核心蛋白聚糖联合治疗显示了在核心蛋白聚糖缺陷动物中治疗人结肠直肠癌细胞的有希望的治疗效果。总的来说，我们的研究结果揭示了结直肠癌的进展，并提供了一种基于蛋白质的治疗方法，即，使用重组核心蛋白聚糖治疗，靶向肿瘤微环境。
The tumor microenvironment encompasses a complex cellular network that includes cancer-associated fibroblasts, inflammatory cells, neo-vessels, and an extracellular matrix enriched in angiogenic growth factors. Decorin is one of the main components of the tumor stroma, but it is not expressed by cancer cells. Lack of this proteoglycan correlates with down-regulation of E-cadherin and induction of β-catenin signaling. In this study, we investigated the role of a decorin-deficient tumor microenvironment in colon carcinoma progression and metastasis. We utilized an established model of colitis-associated cancer by administering Azoxymethane/Dextran sodium sulfate to adult wild-type and Dcn−/− mice. We discovered that after 12 weeks, all the animals developed intestinal tumors independently of their genotype. However, the number of intestinal neoplasms was significantly higher in the Dcn−/− microenvironment vis-à-vis wild-type mice. Mechanistically, we found that under unchallenged basal conditions, the intestinal epithelium of the Dcn−/− mice showed a significant increase in the protein levels of epithelial-mesenchymal transition associated factors including Snail, Slug, Twist, and MMP2. In comparison, in the colitis-associated cancer evoked in the Dcn−/− mice, we found that intercellular adhesion molecule 1 (ICAM-1) was also significantly increased, in parallel with epithelial-mesenchymal transition signaling pathway-related factors. Furthermore, a combined Celecoxib/decorin treatment revealed a promising therapeutic efficacy in treating human colorectal cancer cells, in decorin-deficient animals. Collectively, our results shed light on colorectal cancer progression and provide a protein-based therapy, i.e., treatment using recombinant decorin, to target the tumor microenvironment.
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DOI：
10.1016/j.matbio.2017.10.005
发表时间：
2019-01
期刊：
Matrix biology : journal of the International Society for Matrix Biology
影响因子：
--
作者：
Buraschi S;Neill T;Iozzo RV
通讯作者：
Iozzo RV
影响因子：
6.9
作者：
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通讯作者：
Iozzo, Renato V.
DOI：
10.1038/labinvest.2010.172
发表时间：
2011-03
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
通讯作者：
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影响因子：
4.4
作者：
DANIELSON, KG;FAZZIO, A;IOZZO, RV
通讯作者：
IOZZO, RV
DOI：
10.1093/jnci/djj441
发表时间：
2006-11-15
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Bix, Gregory;Castello, Remedios;Iozzo, Renato V.
通讯作者：
Iozzo, Renato V.